Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka.
J Pharmacol Exp Ther. 2011 Feb;336(2):533-9. doi: 10.1124/jpet.109.165308. Epub 2010 Nov 12.
The purpose of this study was to evaluate the involvement of endothelin (ET)(B) receptor-mediated action in the sex differences in balloon injury-induced neointimal formation using the spotting-lethal rat, which carries a naturally occurring deletion in its ET(B) receptor gene. Male and female ET(B)-deficient and wild-type rats underwent balloon injury of the carotid artery. In the wild-type rats, the neointima/media ratio was significantly lower in females than in males, but this sex difference was attenuated by ovariectomy and restored by treatment with 17β-estradiol (20 μg/kg/day). In the ET(B)-deficient rats, the neointima/media ratio of the male and female rats was markedly increased to the same level, and this increase was not affected by ovariectomy or 17β-estradiol treatment. Treatment with (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (J-104132) (10 mg/kg/day), an ET(A)/ET(B) dual receptor antagonist, markedly decreased the neointima/media ratio of the male wild-type rats and the male and female ET(B)-deficient rats, but not the female wild-type rats. In addition, 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (A-192621) (30 mg/kg/day), a selective ET(B) receptor antagonist, abolished the sex difference of balloon injury-induced neointimal formation. 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627) (10 mg/kg/day), a selective ET(A) receptor antagonist, and J-104132 (10 mg/kg/day) markedly decreased the neointima/media ratio to the same extent in males but not intact females. These results indicate that the sex difference in balloon injury-induced neointimal formation was abolished by genetic ET(B) receptor deficiency or its pharmacological blockade. The lack of a vasoprotective effect of estrogen and the augmentation of ET(A) receptor-mediated action seem to be responsible for the abolition of sex differences in the ET(B) receptor-inhibited condition.
本研究旨在评估内皮素（ET）（B）受体介导的作用在球囊损伤诱导的新生内膜形成中的性别差异中的作用，为此使用了一种天然缺失 ET（B）受体基因的斑点致死大鼠。雄性和雌性 ET（B）缺陷型和野生型大鼠接受颈总动脉球囊损伤。在野生型大鼠中，女性的新生内膜/中膜比值明显低于男性，但这种性别差异在卵巢切除术后减弱，并通过用 17β-雌二醇（20 μg/kg/天）治疗得到恢复。在 ET（B）缺陷型大鼠中，雄性和雌性大鼠的新生内膜/中膜比值显著增加到相同水平，并且卵巢切除或 17β-雌二醇治疗并不影响这种增加。（+）-（5S，6R，7R）-2-丁基-7-[2-（（2S）-2-羧基丙基）-4-甲氧基苯基]-5-（3,4-亚甲基二氧基苯基）环戊烯[1,2-b]吡啶-6-羧酸（J-104132）（10 mg/kg/天），一种 ET（A）/ET（B）双重受体拮抗剂，显著降低雄性野生型大鼠和雄性和雌性 ET（B）缺陷型大鼠的新生内膜/中膜比值，但不降低雌性野生型大鼠的新生内膜/中膜比值。此外，2R-（4-丙氧基苯基）-4S-（1,3-苯并二恶唑-5-基）-1-（N-（2,6-二乙基苯基）氨基羰基甲基）-吡咯烷-3R-羧酸（A-192621）（30 mg/kg/天），一种选择性 ET（B）受体拮抗剂，消除了球囊损伤诱导的新生内膜形成的性别差异。2R-（4-甲氧基苯基）-4S-（1,3-苯并二恶唑-5-基）-1-（N,N-二（正丁基）氨基羰基甲基）-吡咯烷-3R-羧酸（ABT-627）（10 mg/kg/天），一种选择性 ET（A）受体拮抗剂，和 J-104132（10 mg/kg/天），在雄性中显著降低新生内膜/中膜比值，但在完整的雌性中没有降低。这些结果表明，球囊损伤诱导的新生内膜形成中的性别差异在基因 ET（B）受体缺陷或其药理学阻断时被消除。雌激素缺乏血管保护作用和 ET（A）受体介导作用的增强似乎是消除 ET（B）受体抑制条件下性别差异的原因。
